Hao Yanzhong, Li Yaqiao, Zang Wenfeng, Sun Yixin, Li Xin, Li Lin, He Zhonggui, Sun Bingjun
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China; Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
J Colloid Interface Sci. 2025 Apr 15;684(Pt 1):97-108. doi: 10.1016/j.jcis.2025.01.006. Epub 2025 Jan 4.
Doxorubicin (DOX) is a vital anthracycline chemotherapeutic drug, yet presenting significant challenges due to its severe cardiotoxicity. While Doxil enhances the pharmacokinetics and reduces the cardiotoxicity of DOX solution (DOX sol), it shows limitations of low drug loading capacity and inadequate cellular uptake. To overcome these issues, this study developed a novel disulfide bond-linked DOX-maleimide prodrug (DSSM). DSSM could self-assemble into nanoparticles (NPs) with a high drug loading capacity (58.89 %, w/w). DSSM could rapidly bind to endogenous albumin through the maleimide group. Compared to DOX sol, DSSM had increased area under the curve (AUC) by approximately 60-fold, and similarly, quadrupled tumor accumulation after 4 h of administration, achieving efficient tumor targeting. With only 5 % DSPE-mPEG, the cellular uptake of DSSM NPs was better than Doxil. Furthermore, the high reduction sensitivity of the disulfide bond enabled bio-activation of DSSM at the tumor site, while maintaining stability in normal cells. Compared with DOX sol and Doxil, DSSM NPs significantly improved safety and demonstrated better anti-tumor effect at tolerated doses. Our findings present a promising strategy for achieving effective tumor targeting and bio-activation, addressing key limitations of current DOX nanoformulations.
阿霉素（DOX）是一种重要的蒽环类化疗药物，但因其严重的心脏毒性而面临重大挑战。虽然多柔比星脂质体（Doxil）改善了药代动力学并降低了阿霉素溶液（DOX sol）的心脏毒性，但它存在药物负载能力低和细胞摄取不足的局限性。为了克服这些问题，本研究开发了一种新型的二硫键连接的阿霉素-马来酰亚胺前药（DSSM）。DSSM可以自组装成具有高药物负载能力（58.89%，w/w）的纳米颗粒（NPs）。DSSM可以通过马来酰亚胺基团与内源性白蛋白快速结合。与DOX sol相比，DSSM的曲线下面积（AUC）增加了约60倍，同样，给药4小时后肿瘤蓄积增加了四倍，实现了有效的肿瘤靶向。仅使用5%的二硬脂酰磷脂酰乙醇胺-聚乙二醇（DSPE-mPEG），DSSM NPs的细胞摄取就优于Doxil。此外，二硫键的高还原敏感性使DSSM在肿瘤部位实现生物活化，同时在正常细胞中保持稳定性。与DOX sol和Doxil相比，DSSM NPs显著提高了安全性，并在耐受剂量下表现出更好的抗肿瘤效果。我们的研究结果提出了一种实现有效肿瘤靶向和生物活化的有前景的策略，解决了当前DOX纳米制剂的关键局限性。
